US5595738A - CTAA 81AV78, the antigen recognized by human monoclonal antibody 81AV78 - Google Patents

CTAA 81AV78, the antigen recognized by human monoclonal antibody 81AV78 Download PDF

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US5595738A
US5595738A US08/150,036 US15003693A US5595738A US 5595738 A US5595738 A US 5595738A US 15003693 A US15003693 A US 15003693A US 5595738 A US5595738 A US 5595738A
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ctaa
cells
antigen
methanol
tumor cell
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Nicholas Pomato
Janet H. Ransom
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Per Immune Holdings Inc
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Akzo Nobel NV
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • C07K16/3046—Stomach, Intestines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Colorectal cancer is the second most prevalent cancer in the United States, affecting both men and women.
  • the only viable treatment for this disease has been surgery, which has a poor prognosis for patients with transmural extension of tumor and metastasis to regional lymph nodes.
  • a dramatically improved prognosis was indicated in a recently reported randomized Phase II-active specific immunotherapy trial, which showed that immunization of patients with autologous tumor cells admixed with Tice BCG (Bacillus Calmette Guerin) (Institute for Tuberculosis Research, Chicago, Ill.) significantly increased delayed cutaneous hypersensitivity responses and, over a four year period of time, significantly decreased recurrence and mortality.
  • Tice BCG Bath Calmette Guerin
  • colon carcinoma-associated antigens There have been numerous publications describing the identification of colon carcinoma-associated antigens. The majority of these antigens were identified using monoclonal antibodies generated by immunizing mice with some form of the colon tumor (extracts, dissociated cells, membrane preparations, and etc.) or colon tumor cell lines. These mouse antibodies identify a repertoire of antigens that were antigenic in the mouse. In addition to these studies, there are several reports of human monoclonal antibodies that show specific reactivity with tumor material.
  • peripheral blood B-cells from colorectal patients actively immunized with autologous tumor cells and BCG in immunotherapy protocols we have successfully developed a strategy for producing human anti-tumor monoclonal antibodies.
  • human monoclonal antibodies generated against human colon cancer which often recognize tissue components also found in healthy individuals, such as CEA
  • our human monoclonal antibodies exhibit no reactivity with CEA, blood group determinants or histocompatibility antigens, indicating that these antibodies are characterized by a specificity confined to those epitopes that are recognized as immunogenic in the autologous host.
  • CTAA 81AV78 is a tumor associated antigen recognized by the human monoclonal antibody 81AV78 claimed in copending application U.S. Ser. No. 07/701,281 filed May 16, 1991 for Tumor Associated Monoclonal Antibody 81AV78, by Hanna et al., and included herein by reference.
  • This IgM monoclonal antibody is found to be reactive with a cell surface antigen in various tumor cell lines.
  • CTAA 81AV78 is found in lipid extracts of colon tumor cell lines, primary colon tumors, and colon tumor xenograft tissues.
  • the antigen has been found to be acidic in nature and can be purified by various thin layer chromatographic and column chromatographic techniques.
  • the invention also relates to the use of antibodies to the antigen containing this epitope for diagnosis and monitoring of treatment of cancer and to the use of this antigen in the preparation of vaccines to elicit an immune response similar to that obtained against tumor cells containing this epitope.
  • FIGS. 1A-1D show two dimensional TLC of two sets of tumor FIGS. 1C and 1D) and normal tissue (FIGS. 1A and 1B). These figures show the CTAA 81AV78-4A and CTAA 81AV78-5 are present in tumor tissue extracts but were not found in normal colon tissue extract.
  • FIG. 2 Purity of CTAA 81AV78-4A and 5 By TLC.
  • FIG. 3 Immunoreactivity of CTAA 81AV78-4A and 5 With MCA 81AV78.
  • FIG. 4 CTAA 81AV78-4A and 5 purified by thin layer chromatography Are Positive For Phosphate Groups After TLC.
  • FIG. 5 is the NMR spectrum of CTAA 81AV78-4A.
  • FIG. 5A is an expansion of the NMR of FIG. 5 between about 2.5 and 0.5 PPM to better show the unsaturated fatty acid side chain at 2.0 PPM.
  • FIG. 5B is an expansion of the NMR of FIG. 5, and better shows the alpha and gamma resonances between about 3.5 and 4.5 PPM (the insert in FIG. 5B shows the beta resonances between about 5.5 and 5.0 on FIG. 5).
  • FIG. 6 is the Fast Atom Bombardment (FAB)-Mass Spectrometer Spectra of CTAA 81AV78-4A.
  • FIG. 6A is an expansion of the region of FIG. 6 between 200 and 350, showing the presence of fatty acids.
  • FIG. 6B is an expansion of FIG. 6 between 1200 and 1500, showing the molecular masses in better detail.
  • FIG. 7 shows the NMR Spectrum of CTAA 81AV78-5.
  • FIG. 8 is the Fast Atom Bombardment (FAB)-Mass Spectrometer Spectra of CTAA 81AV78-5.
  • FIG. 8A is an expansion of the region of FIG. 8 between 200 and 350, showing the presence of fatty acids.
  • FIG. 8B is an expansion of FIG. 8 between 600 and 900, showing the molecular masses in better detail.
  • FIG. 9 illustrates the NMR Spectrum of Bovine Heart Cardiolysin.
  • FIG. 10 illustrates the NMR Spectrum of Mono-oleoyl-phosphatidic Acid.
  • Lipids from colon tumor cell lines and primary colon tumors have been found to be reactive with the human monoclonal antibody 81AV78.
  • the lipids were purified by column chromatography and thin layer chromatographic methods.
  • the purified lipids were found to be acidic phospholipids that did not appear to be glycosylated.
  • Two lipids comprising the antigen were identified and characterized by their migration in various thin layer chromatographic systems. Since at least one of the two lipids causes proliferation of T-cells, this antigen is a good candidate for use in a vaccine to elicit cell mediated immune responses to various types of cancer.
  • Crude lipids were extracted from tumor cell lines or primary colon tumors using chloroform-methanol extraction (2:1). The crude lipid fraction was found to have immunoreactive spots when tested in one dimensional thin layer chromatography. Separation of the neutral from the acidic lipids using DEAE Sephadex anion exchange chromatography indicated that the immunoreactive lipids were found in the lipids that bound to this column. Thus, the immunoreactive lipids were located in the acidic pool of lipids after extraction and fractionation.
  • the immunoreactive lipids recognized by the human monoclonal antibody 81AV78 have been designated CTAA 81AV78-4A and CTAA 81AV78-5.
  • CTAA 81AV78-4A The immunoreactive lipids recognized by the human monoclonal antibody 81AV78 have been designated CTAA 81AV78-4A and CTAA 81AV78-5.
  • FIG. 1 shows the results of two sets of tumor tissues and normal colon tissues that had been extracted and analyzed by two dimensional TLC using chloroform-methanol solvent in the first dimension and butanol-pyridine solvent in the second dimension. Various spots were identified on these chromatograms by charring.
  • the two acidic lipids were purified to apparent homogeneity after extraction from tumor cell lines using anion exchange chromatography followed by preparative thin layer chromatography.
  • Table 5 reports the relative quantity of the two lipids purified from eight different tumor cell lines obtained from the American Type Culture Collection, which indicates that most tumor cell lines showed sufficient expression of these lipids such that they could be purified from cellular material.
  • the solvent system used for purification was the butanol-pyridine system. Lipids were cut out from thin layer chromatograms and eluted from the silica gel with chloroform-methanol. As shown in FIG. 2, when the extracted lipids were rechromatographed a single spot was obtained for each of the lipids.
  • the purified lipids were then rechromatographed and examined for immunoreactivity with MCA 81AV78. As shown in FIG. 3, immunoreactive spots were observed for both the CTAA 81AV78-4A and the CTAA 81AV78-5 .
  • both antigens were subjected to thin layer chromatography in multiple solvent systems. The antigens were tested both in purified and in crude acidic form.
  • Table 1A summarizes the R f values for CTAA 81AV78-4A in three solvent systems.
  • Table 1B summarizes the R f values for CTAA 81AV78-5 in the same solvent systems.
  • T-cell proliferative assays were performed on peripheral blood lymphocytes from patients undergoing active specific immunotherapy. As shown in Table 3, CTAA 81AV78-4A elicited T-cell proliferative responses in the PBL of two patients who had been immunized with autologous tumor cells. This indicates that this antigen is a candidate for vaccine development.
  • the tumor cell lines WiDr and HCT-8 were obtained from the American Type Tissue Culture Collection (ATCC), Rockville, Md. Primary colon tumors were obtained after surgical removal from the Washington Hospital, Washington, D.C.
  • This layer chromatography plates are designated as HPTLC-KIESELEG 60 (EM Sciences, Gibbstown, N.J., Catalog Number 5547).
  • the first solvent system used was: chloroform-methanol, calcium chloride, and ammonium hydroxide at volume ratios of 30:20:3.2 (v/v/v), respectively.
  • the second system used was butanol, pyridine, and 30% ammonium hydroxide solution at volume ratios of 30:47.5:5.75 (v/v/v).
  • a third solvent system used was propanol, hexanol and water at volume ratios of 25:25:3 (v/v/v). In general, samples were spotted onto the chromatographic plates, which were then placed in a chromatography chamber.
  • DEAE-Sephadex was obtained from Pharmacia, Inc., Piscatawy, N.J.
  • High performance liquid chromatography SI-60 Silica column was obtained from Suppelco, Inc.
  • lipid extracts were loaded onto the column, which had previously been equilibrated in 100% methanol.
  • the lipids that stuck to the column were eluted with 100% methanol containing 0.3M ammonium acetate.
  • silica SI-60 column samples were loaded on the column that had previously been equilibrated with propanol-hexanol at a 1:1 ratio.
  • the column was then eluted with a linear gradient of propanol-hexanol containing 4% water to propanol containing 9% water. All solvent buffers contained 0.005% ascetic acid.
  • Immunoreactivity of the lipid antigen was demonstrated using MCA 81AV78. Approximately 40 ⁇ g of purified lipids or 100-20 ⁇ g of crude acidic lipids were spotted on TLC plates using the chloroform-methanol solvent system. All solutions used contained 3% polyvinylpyrrolidone (Amresco, Solon, Ohio Catalog Number P0050720). The plates were dried and then blocked with blotto (5% w/v of non-fat dry milk in phosphate buffered saline [PBS]) for 1 hour. After washing 3 ⁇ in PBS, the plate was incubated with MCA 81AV78 diluted to 10 ⁇ g/ml in PBS at 23° C. for 1 hour.
  • PBS phosphate buffered saline
  • T-cell proliferative assays were performed using the peripheral blood lymphocytes (PBL) from patients who had been immunized with their own tumor cells. PBL were stored at -70° C. and then thawed and plated in microtiter plates at a density of 5 ⁇ 10 4 cells per well. The test antigens were added at concentrations of 20 ⁇ g to 200 ⁇ g per well. Thirty units/ml of gamma-interferon were added per well. Cells were incubated for six days, pulsed for 16 hour with [ 3 H]-thymidine, collected onto filters and counted. The stimulation index (S.I.) was calculated as follows: ##EQU1## For these experiments, purified protein derivative (PPD) was used as a control.
  • PPD peripheral blood lymphocytes
  • the pure antigen fractions, 5 (CTAA 81AV78-5) and 4A (CTAA 81AV78-4A) were further analyzed by 1 H-NMR, FAB-MS and fatty acid analysis.
  • the 1 H-NMR spectrum of 4A is shown in FIG. 5.
  • the glycerol backbone proton resonances ⁇ , ⁇ and ⁇ are illustrative of a phosphatidic acid core structure, i.e., both ⁇ - and ⁇ -hydroxyl functions are acylated (R 1 and R 2 ), while the ⁇ -hydroxyl function is phosphorylated. ##STR1##
  • FAB-MS spectra FIG. 6, provided molecular masses of 1344, 1372, 1400 and 1488, and identified the presence of the fatty acids 16:0, 16:1, 18:0 and 18:1.
  • the 1 H-NMR spectrum of fraction 5 is shown in FIG. 7.
  • the glycerol backbone proton resonances ⁇ , ⁇ and ⁇ are characteristic of a lysophosphatidic acid core structure, i.e., lacking an acyl chain at the ⁇ -hydroxyl function.
  • FIG. 10 See FIG. 10 for a reference spectrum for mono-oleoyl-lysophosphatidic acid, to be compared ( ⁇ , ⁇ and ⁇ resonances) with FIG. 7.

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Cited By (6)

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US5824555A (en) * 1996-05-30 1998-10-20 The Cleveland Clinic Foundation Method of detecting gynecological carcinomas
US6451609B1 (en) 1996-05-30 2002-09-17 The Cleveland Clinic Foundation Method of detecting gynecological carcinomas
WO2003022870A1 (en) * 2001-09-12 2003-03-20 Eastern Virginia Medical School Calcium-influx inhibitory factor and method of isolation thereof
US20050249667A1 (en) * 2004-03-24 2005-11-10 Tuszynski Jack A Process for treating a biological organism
US20070092549A1 (en) * 2003-10-31 2007-04-26 Tuszynski Jack A Water-soluble compound
US20080313401A1 (en) * 2006-12-20 2008-12-18 Byung Suk Kang Device for Processing Information and Working Method Thereof

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US6087174A (en) * 1996-12-26 2000-07-11 Johns Hopkins University, School Of Medicine Growth medium for primary pancreatic tumor cell culture

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ATE179331T1 (de) 1999-05-15
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